In general, it is feared that a non-steroidal antiphlogistic and analgesic drugs (or anti-inflammatories) cause side effects when they are administrated orally or rectally. For the purpose of solving the side effects, a wide variety of pharmaceutical preparations for external use which are administrated directly in topical portions have been developed. In many such pharmaceutical preparations, since most non-steroidal antiphlogistic and analgesic drugs do not easily dissolve in both water and oil, lower alcohols, polyvalent alcohols, fatty acid esters, crotamiton, surfactants, or the like are combined to dissolve the drugs or the medicine is dispersed in a medium in micro-powder form such as crystal, and then water-soluble polymeric compounds are formulated in order to ensure the stabilization of the dispersion. Even the salt compounds of the non-steroidal antiphlogistic and analgesic drugs in the form of sodium salts are only slightly soluble in water, and thus attempts to use various methods have been made for preparation.
With examples of the method, since skin safety is generally lowered when a lower alcohol or a polyhydric alcohol such as propylene glycol is formulated in a large amount for the purpose of dissolving the medicine, an aqueous emulsified preparation not using any lower alcohol has been proposed (see, for example, Japanese Unexamined Patent Publications (Kokai) No. 57-98209, No. 58-185514, No. 59-116212 and No. 61-215320). In almost all of these inventions, the dispersion is thickened with a water-soluble polymeric compound, and thus it is very difficult to enhance their thermodynamic activities in terms of the separation of the medicine with the passage of time and the discharge of the medicine. Further, because of stickiness due to a large amount of the water-soluble polymeric compound being formulated, it is not preferred from the viewpoint of its texture. On the other hand, for the purpose of enhancing the discharge of the medicine from the base, an invention in which the medicine is prepared in the saturated state (see Japanese Unexamined Patent Publication (Kokai) No. 63-150221) has been disclosed. Due to the formulation of a higher alcohol, the invention, however, has the problem that the esterification reaction with the medicine causes a significant impairment in the compound's stability. In particular, in the case where the medicine has a low stable pH region, it is apt to bring about the esterification with the higher alcohol, the reaction being increasingly likely to occur when the water formulation is larger. On the other hand, since there is poor solubility in water even when the non-steroid agent is a salt (or a compound in the form of the salt), the invention in which the preparation is made into an oleaginous ointment has been known (see Japanese Unexamined Patent Publication (Kokai) No. 59-33211). The agent thus prepared is unduly greasy and tends to stain clothes; thus, it is not necessarily preferred. Furthermore, Inventions of a cream preparation (see Japanese Unexamined Patent Publication (Kokai) No. 64-13020) and a solution preparation (see Japanese Unexamined Patent Publication (Kokai) No. 1-242521) have been disclosed.
However, in preparation of the cream, the water-soluble polymeric compound or a higher alcohol is used, and thus preparations using the compounds as described above are associated with common problems.
Also, to provide a cream or ointment, it is known that a pharmaceutical preparation for external use contains a combination of .alpha.-monoglyceryl ether and an oily substance in the form of paste as well as a biological active substance of percutaneous absorption (see Japanese Examined Patent Publication (Kokoku) 2-44815), and that an oil-in-water type emulsifying stabilizer consists of N-long chain acyl acidic amino acids and glycerol monoalkyl ethers. The former increases the percutaneous absorption by increasing occlusion. Accordingly, the publication discloses mainly preparations belonging to water-in-oil (w/o) as a type of emulsifying agent. Although this preparation is improved to some degree, the preparation is greasy. Further, the preparation is only used as a lipophilic surface-active agent, and thus it is very difficult to emulsify the same because the surface-active agent is dissolved in a higher polar oil ingredient when the oil is used in a large amount to dissolve the medicine. Accordingly, it is difficult for a medicine in the form of a salt, such as diclofenac sodium, to be stable at a high concentration. Although the latter is in a stable state to the emulsified composition itself, the emulsifying stabilizer, is not sufficiently effective as can be seen from the components thereof when the stabilizer is applied to a medicine which may be unstabilized in acidic condition.
Although the aforementioned emulsified compositions and pharmaceutical preparations independently solve certain problems, they are not entirely satisfactory in application or stability.
Accordingly, the object of the present invention is to provide a useful pharmaceutical preparation for external use with an emulsified composition which has excellent texture and belongs to a o/w type, and comprises a non-steroidal antiphlogistic and analgesic drug.